Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.
10.1016/j.apsb.2019.09.007
- Author:
Kaijun JIN
1
;
Minjie LIU
1
;
Chunlin ZHUANG
1
;
Erik DE CLERCQ
2
;
Christophe PANNECOUQUE
2
;
Ge MENG
1
;
Fener CHEN
1
Author Information
1. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433 China.
2. Rega Institute for Medical Research, KU Leuven, Leuven B-3000 Belgium.
- Publication Type:Journal Article
- Keywords:
AIDS, acquired immunodeficiency syndrome;
BP-DATA, biphenyl-substituted diaryltriazine;
BP-DATAs;
CC50, 50% cytotoxicity concentration;
DAPY, diarylpyrimidine;
DATA, diaryltriazine;
EC50, the concentration causing 50% inhibition of antiviral activity;
EFV, efavirenz;
ETR, etravirine;
HEPT, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine;
HIV, human immunodeficiency virus;
HIV-1;
MD, molecular dynamic;
Molecular modeling;
NNIBP, non-nucleoside inhibitor binding pocket;
NNRTI, non-nucleoside reverse transcriptase inhibitor;
NNRTIs;
NP-DATA, naphthyl diaryltriazine;
NP-DATAs;
NVP, nevirapine;
PK, pharmacokinetics;
Positional adaptability;
RMSD, root-mean square deviation;
RPV, rilpivirine;
RT, reverse transcriptase;
SAR, structure–activity relationship;
SI, selectivity index;
TSAO, tert-butyldimethylsilyl-spiroaminooxathioledioxide;
WT, wild-type
- From:
Acta Pharmaceutica Sinica B
2020;10(2):344-357
- CountryChina
- Language:English
-
Abstract:
In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds and had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure-activity relationship and PK profiles were also discussed.
